G protein-coupled receptors (GPCR) comprise a membrane protein family and are the primary cellular sensors for external chemical stimuli. The non-sensory subset of the rhodopsin family GPCR still includes nearly 70 orphan receptors, for which endogenous signaling molecules (agonists) are not yet defined. The orphan GPCR, GPR88, plays an important role in motor coordination and learning, and has been genetically associated with schizophrenia and bipolar disorder. Identification of the natural agonist that activates GPR88 would open the door toward a better understanding of the molecular events that lead to these devastating psychiatric diseases. In this project, we will use our computational model of GPR88 to guide our identification of the native ligand of the orphan GPCR, GPR88. We will use the same approach to identify drug-like antagonists of GPR88 to launch a new paradigm in schizophrenia and bipolar disorder drug discovery efforts. In order to reach this objective, we will divide the approach into three specific aims. In the first we will extend and validate our preliminary model of GPR88 using the Rosetta LoopModeler module and docking studies of the currently known synthetic agonists to define testable hypotheses regarding amino acid roles in agonist recognition that we will test using site-directed mutagenesis. In the second we will utilize docking studies of candidate naturally-occurring amines to prioritize candidate natural agonists for experimental assays to deorphanize GPR88. In the third aim we will utilize a similar approach to prioritize and evaluate candidate drug-like molecules for assessment as GPR88 antagonists.